Compositions and treatment for diabetic complications

ABSTRACT

This invention is directed to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective COX-2 inhibitor, a prodrug thereof or a pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug. This invention further relates to methods of using those pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy.

This application is filed claiming priority from co-pending ProvisionalApplication No. 60/141,746 filed Jun. 30, 1999.

BACKGROUND OF THE INVENTION

This invention relates to methods, pharmaceutical compositions and kitscomprising an aldose reductase inhibitor (ARI), a prodrug thereof or apharmaceutically acceptable salt of said ARI or said prodrug and aselective cyclooxygenase-2 (COX-2) inhibitor, a prodrug thereof or apharmaceutically acceptable salt of said selective COX-2 inhibitor orsaid prodrug. This invention further relates to methods of using suchpharmaceutical compositions for the treatment of diabetic complicationssuch as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,myocardial infarction, cataracts and diabetic cardiomyopathy.

Aldose reductase inhibitors function by inhibiting the activity of theenzyme aldose reductase, which is primarily responsible for regulatingthe reduction of aldoses, such as glucose and galactose, to thecorresponding polyols, such as sorbitol and galactitol, in humans andother animals. In this way, unwanted accumulations of galactitol in thelens of galactosemic subjects and of sorbitol in the lens, peripheralnervous cord and kidneys of various diabetic subjects are prevented orreduced. Accordingly, aldose reductase inhibitors are of therapeuticvalue for controlling certain diabetic complications, e.g., diabeticneuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardialinfarction, cataracts and diabetic retinopathy.

Two forms of cylcooxygenase (COX) are known to exist: COX-1 and COX-2,the former being a constitutive form and the latter being an inducibleform. COX-1 exists in the stomach, intestines, kidneys and plateletswhile COX-2 is expressed during inflammation. Both COX enzyme isoformsmetabolize arachidonic by a similar mechanism, but each have differentsubstrate specificities. Selective COX-2 inhibitors are advantageous inthe treatment of pain and inflammation while avoiding such side effectsas gastric and renal toxicity.

SUMMARY OF THE INVENTION

This invention is directed to pharmaceutical compositions comprising analdose reductase inhibitor (ARI), a prodrug thereof or apharmaceutically acceptable salt of said ARI or said prodrug; (a) aselective COX-2 inhibitor of formula I,

wherein R¹ is sulfamyl;

R² is haloalkyl;

R³ is selected from hydrido and alkyl; and

R⁴ is selected from aryl, cycloalkyl and cycloalkenyl; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, alkylthio, alkylsulfinyl, alkyl,alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl,hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl,amino, N-alkylamino, N,N-dialkylamino, heterocyclic, nitro andacylamino;

or a prodrug thereof or a pharmaceutically acceptable salt thereof or ofsaid prodrug;

or (b) a COX-2 inhibitor of formula II,

 wherein R⁵ is selected from alkyl, carboxyalkyl, alkoxycarbonyl,aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl,alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio,cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl,aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl,hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio,alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl,alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl;

R⁶ is selected from cycloalkyl, cycloalkenyl and aryl; wherein R⁶ isoptionally substituted at a substitutable position with one or moreradicals independently selected from alkyl, cyano, carboxyl,alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and

R⁷ is selected from lower alkyl, hydroxyl and amino; a prodrug thereofor a pharmaceutically acceptable salt thereof or of said prodrug;

and a pharmaceutically acceptable carrier, vehicle or diluent.

This invention is also directed to methods of treating a diabeticcomplication in a mammal comprising administering to said mammal apharmaceutical composition as set forth hereinabove. In particular, suchdiabetic complications as, for example, diabetic neuropathy, diabeticnephropathy, diabetic cardiomyopathy, myocardial infarction, cataractsand diabetic retinopathy can be treated by the methods of thisinvention.

This invention is also directed to kits comprising:

a) a first unit dosage form comprising an aldose reductase inhibitor(ARI), a prodrug thereof or a pharmaceutically acceptable salt of saidARI or said prodrug and a pharmaceutically acceptable carrier, vehicleor diluent;

b) A second unit dosage form comprising a selective COX-2 inhibitor offormula I,

wherein R¹ is sulfamyl;

R² is haloalkyl;

R³ is selected from hydrido and alkyl; and

R is selected from aryl, cycloalkyl and cycloalkenyl; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, alkylthio, alkylsulfinyl, alkyl,alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl,hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl,amino, N-alkylamino, N,N-dialkylamino, heterocyclic, nitro andacylamino;

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; or a COX-2 inhibitor of formula II,

 wherein R⁵ is selected from alkyl, carboxyalkyl, alkoxycarbonyl,amrinocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl,alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio,cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl,aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl,hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio,alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl,alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl;

R⁶ is selected from cycloalkyl, cycloalkenyl and aryl; wherein R⁶ isoptionally substituted at a substitutable position with one or moreradicals independently selected from alkyl, cyano, carboxyl,alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and

R⁷ is selected from lower alkyl, hydroxyl and amino;

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; and

c) a container.

This invention is also directed to methods of treating a diabeticcomplication in a mammal comprising administering to said mammal an ARI,a prodrug thereof or a pharmaceutically acceptable salt of said ARI orsaid prodrug; and (a) a selective COX-2 inhibitor of formula I

wherein R¹ is sulfamyl;

R² is haloalkyl;

R³ is selected from hydrido and alkyl; and

R⁴ is selected from aryl, cycloalkyl and cycloalkenyl; wherein R⁴ isoptionally substituted at a substitutable position with one or moreradicals selected from halo, alkylthio, alkylsulfinyl, alkyl,alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido, N-monoalkylamido,N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, haloalkyl,hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylsulfamyl,amino, N-alkylamino, N,N-dialkylamino, heterocyclic, nitro andacylamino;

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug; or (b) a COX-2 inhibitor of formula II,

 wherein R⁵ is selected from alkyl, carboxyalkyl, alkoxycarbonyl,aminocarbonyl, aminocarbonylalkyl, alkoxycarbonylalkyl, carboxyl,alkoxy, haloalkoxy, aralkoxy, cycloalkylalkoxy, alkylthio, aralkylthio,cycloalkylalkylthio, alkoxyalkyl, aralkoxyalkyl, alkylthioalkyl,aralkylthioalkyl, alkylaminoalkyl, aryloxyalkyl, arylthioalkyl,hydroxyl, amino, hydroxyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aralkyl, halo, alkylamino, aralkylamino, N-alkyl-N-aralkylamino,N-alkyl-N-cycloalkylalkylamino, arylcarbonyloxyalkyl, arylcarbonylthio,alkoxycarbonyloxyalkyl, alkylaminocarbonyloxyalkyl,alkoxycarbonylthioalkyl and alkylaminocarbonylthioalkyl;

R⁶ is selected from cycloalkyl, cycloalkenyl and aryl; wherein R⁶ isoptionally substituted at a substitutable position with one or moreradicals independently selected from alkyl, cyano, carboxyl,alkoxycarbonyl, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,alkylamino, arylamino, aminoalkyl, nitro, alkoxyalkyl, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, halo, alkoxy and alkylthio; and

R⁷ is selected from lower alkyl, hydroxyl and amino;

a prodrug thereof or a pharmaceutically acceptable salt of said compoundor said prodrug.

It is preferred that the ARI and the selective COX-2 inhibitor areadministered together.

It is also preferred that the ARI and the COX-2 inhibitor areadministered separately in any order.

In the compositions, methods and kits of this invention, it is preferredthat said ARI is fidarestat, epalrestat, minalrestat, SPR-210,zenarastat or zopolrestat, a prodrug of thereof or a pharmaceuticallyacceptable salt of said ARI or of said prodrug. It is especiallypreferred that said ARI is zopolrestat, a prodrug thereof or apharmaceutically acceptable salt of zopolrestat or of said prodrug andsaid COX-2 inhibitor is celecoxib or valdecoxib, a prodrug thereof or apharmaceutically acceptable salt of said selective COX-2 inhibitor or ofsaid prodrug.

Where used herein and in the appendant claims, the phrase “lower alkyl”refers to alkyl groups containing one to four carbon atoms straightchain or branched.

DETAILED DESCRIPTION OF THE INVENTION

The COX-2 inhibitors of formula I, including celecoxib, which are usedin the compositions, methods and kits of this invention are preparedaccording to methods reported in U.S. Pat. No. 5,466,823, which ishereby wholly incorporated herein by reference. Celecoxib is also knownas benzenesulfonamide,4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]- and has thefollowing chemical structure:

The COX-2 inhibitors of formula II, including valdecoxib, which are usedin the compositions, methods and kits of this invention are preparedaccording to methods reported in U.S. Pat. No. 5,633,272, which ishereby wholly incorporated herein by reference. Valdecoxib is also knownas benzenesulfonamide, 4-(5-methyl-3-phenyl-4-isoxazolyl)- and has thefollowing chemical structure:

The methods, compositions and kits of this invention are useful intreating diabetic complications, including, but not limited to, diabeticneuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardialinfarction, cataracts and diabetic retinopathy.

The term “treating”, as used herein, refers to retarding, arresting orreversing the progress of, or alleviating or preventing either thedisorder or condition to which the term “treating” applies, or one ormore symptoms of such disorder or condition. The term “treatment”, asused herein, refers to the act of treating a disorder, symptom orcondition, as the term “treating” is defined above.

Any aldose reductase inhibitor may be used in the pharmaceuticalcompositions, methods and kits of this invention. The term aldosereductase inhibitor refers to a compound which inhibits thebioconversion of glucose to sorbitol catalyzed by the enzyme aldosereductase. Such inhibition is readily determined by those skilled in theart according to standard assays (J. Malone, Diabetes, 29:861-864, 1980.“Red Cell Sorbitol, an Indicator of Diabetic Control”). The followingpatents and patent applications, each of which is hereby whollyincorporated herein by reference, exemplify aldose reductase inhibitorswhich can be used in the compositions, methods and kits of thisinvention, and refer to methods of preparing those aldose reductaseinhibitors: U.S. Pat. No. 4,251,528; U.S. Pat. No. 4,600,724; U.S. Pat.No. 4,464,382, U.S. Pat. No. 4,791,126, U.S. Pat. No. 4,831,045; U.S.Pat. Nos. 4,734,419; 4,883,800; U.S. Pat. No. 4,883,410; U.S. Pat. No.4,883,410; U.S. Pat. No. 4,771,050; U.S. Pat. No. 5,252,572; U.S. Pat.No. 5,270,342; U.S. Pat. No. 5,430,060; U.S. Pat. No. 4,130,714; U.S.Pat. No. 4,540,704; U.S. Pat. No. 4,438,272; U.S. Pat. No. 4,436,745,U.S. Pat. No. 4,438,272; U.S. Pat. No. 4,436,745, U.S. Pat. No.4,438,272; U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272; U.S. Pat.No. 4,980,357; U.S. Pat. No. 5,066,659; U.S. Pat. No. 5,447,946; U.S.Pat. No. 5,037,831.

A variety of aldose reductase inhibitors are specifically described andreferenced below, however, other aldose reductase inhibitors will beknown to those skilled in the art. Also, common chemical USAN names orother designations are in parentheses where applicable, together withreference to appropriate patent literature disclosing the compound.

Accordingly, examples of aldose reductase inhibitors useful in thecompositions and methods of this invention include:

1. 3-(4-bromo-2-fluorobenzyl)-3,4-dihydro-4-oxo-1-phthalazineacetic acid(ponalrestat, U.S. Pat. No. 4,251,528);

2.N[[(5-trifluoromethyl)-6-methoxy-1-naphthalenyl]thioxomethyl}-N-methylglycine(tolrestat, U.S. Pat. No. 4,600,724);

3. 5-[(Z,E)-β-methylcinnamylidene]-4-oxo-2-thioxo-3-thiazolideneaceticacid (epalrestat, U.S. Pat. No. 4,464,382, U.S. Pat. No. 4,791,126, U.S.Pat. No. 4,831,045);

4.3-(4-bromo-2-fluorobenzyl)-7-chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineaceticacid (zenarestat, U.S. Pat. Nos. 4,734,419, and 4,883,800);

5. 2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Pat.No. 4,883,410);

6. 2R,4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid(U.S. Pat. No. 4,883,410);

7. 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid(U.S. Pat. No. 4,771,050);

8.3,4-dihydro-3-oxo-4-[(4,5,7-trifluoro-2-benzothiazolyl)methyl]-2H-1,4-benzothiazine-2-aceticacid (SPR-210, U.S. Pat. No. 5,252,572);

9.N-[3,5-dimethyl-4-[(nitromethyl)sulfonyl]phenyl]-2-methylbenzeneacetamide(ZD5522, U.S. Pat. No. 5,270,342 and U.S. Pat. No. 5,430,060);

10. (S)-6-fluorospiro[chroman-4,4′-imidazolidine]-2,5′-dione (sorbinil,U.S. Pat. No. 4,130,714);

11. d-2-methyl-6-fluoro-spiro(chroman-4′,4′-imidazolidine)-2′,5′-dione(U.S. Pat. No. 4,540,704);

12. 2-fluoro-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione (U.S.Pat. No. 4,438,272);

13. 2,7-di-fluoro-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione(U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);

14.2,7-di-fluoro-5-methoxy-spiro(9H-fluorene-9,4′-imidazolidine)-2′,5′-dione(U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);

15.7-fluoro-spiro(5H-indenol[1,2-b]pyridine-5,3′-pyrrolidine)-2,5′-dione(U.S. Pat. No. 4,436,745, U.S. Pat. No. 4,438,272);

16.d-cis-6′-chloro-2′,3′-dihydro-2′-methyl-spiro-(imidazolidine-4,4′-4′H-pyrano(2,3-b)pyridine)-2,5-dione(U.S. Pat. No. 4,980,357);

17.spiro[imidazolidine-4,5′(6H)-quinoline]-2,5-dione-3′-chloro-7,′8′-dihydro-7′-methyl-(5′-cis)(U.S. Pat. No. 5,066,659);

18.(2S,4S)-6-fluoro-2′,5′-dioxospiro(chroman-4,4′-imidazolidine)-2-carboxamide(fidarestat, U.S. Pat. No. 5,447,946); and

19.2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H),3′-pyrrolidine]-1,2′,3,5′(2H)-tetrone(minalrestat, U.S. Pat. No. 5,037,831).

All of the foregoing patents disclosing ARI compounds are whollyincorporated herein by reference.

Other aldose reductase inhibitors include compounds of formula A,

and pharmaceutically acceptable salts thereof, wherein

Z in the compound of formula A is O or S;

R¹ in the compound of formula A is hydroxy or a group capable of beingremoved in vivo to produce a compound of formula A wherein R¹ is OH; and

X and Y in the compound of formula A are the same or different and areselected from hydrogen, trifluoromethyl, fluoro, and chloro.

A preferred subgroup within the above group of aldose reductaseinhibitors includes numbered compounds 1, 2, 3, 4, 5, 6, 9, 10, and 17,and the following compounds of formula A:

20.3,4-dihydro-3-(5-fluorobenzothiazol-2-ylmethyl)-4-oxophthalazin-1-yl-aceticacid [R¹=hydroxy; X=F; Y=H];

21.3-(5,7-difluorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=F];

22.3-(5-chlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Cl; Y=H];

23.3-(5,7-dichlorobenzothiazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=Cl];

24.3,4-dihydro-4-oxo-3-(5-trifluoromethylbenzoxazol-2-ylmethyl)phthalazin-1-ylaceticacid [R¹=hydroxy; X=CF₃; Y=H];

25.3,4-dihydro-3-(5-fluorobenzoxazol-2-ylmethyl)-4-oxophthalazin-1-yl-aceticacid [R¹=hydroxy; X=F; Y=H];

26.3-(5,7-difluorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=F];

27.3-(5-chlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Cl; Y=H];

28.3-(5,7-dichlorobenzoxazol-2-ylmethyl)-3,4-dihydro-4-oxophthalazin-1-ylaceticacid [R¹=hydroxy; X=Y=Cl]; and

29. zopolrestat; 1-phthalazineacetic acid,3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-[R¹=hydroxy; X=trifluoromethyl; Y=H].

In compounds 20-23 and 29, Z is S. In compounds 24-28, Z is O.

Of the above subgroup, compounds 20-29 are more preferred with compound29 especially preferred.

Said compounds of formula A are prepared as disclosed in U.S. Pat. No.4,939,140, which is wholly incorporated herein by reference.

The aldose reductase inhibitor compounds of this invention are readilyavailable or can be easily synthesized by those skilled in the art usingconventional methods of organic synthesis, particularly in view of thepertinent patent specifications.

The activity of the selective COX-2 inhibitors of the present inventionmay be demonstrated by the following assays. COX-1 activity isdetermined by methods well known to those skilled in the art. The humancell based COX-2 assay is carried out as previously described (Moore etal., Inflam. Res., 45, 54,1996). The in vivo Carrageenan induced footedema rat study is carried out as previously described in Winter et al.,Proc. Soc. Exp. Biol. Med., 111, 544, 1962.

COX-2 selectivity can be determined by methods well known to thoseskilled in the art and particularly by ratio in terms of IC₅₀ value ofCOX-1 inhibition to COX-2 inhibition. In general, it can be said that acompound showing a COX-1/COX-2 inhibition ratio of more than 2 has goodCOX-2 selectivity.

This invention relates both to methods of treating diabeticcomplications in which the ARI, prodrug thereof or pharmaceuticallyacceptable salt of said ARI or said prodrug and said selective COX-2inhibitor, prodrug thereof or pharmaceutically acceptable salt of saidselective COX-2 inhibitor or said prodrug are administered together, aspart of the same pharmaceutical composition, and to methods in whichthese two active agents are administered separately, as part of anappropriate dosage regimen designed to obtain the benefits of thecombination therapy. The appropriate dosage regimen, the amount of eachdose administered and the intervals between doses of the active agentswill depend upon the ARI and the selective COX-2 inhibitor being used,the type of pharmaceutical formulations being used, the characteristicsof the subject being treated and the severity of the complications.Generally, in carrying out the methods of this invention, an effectivedosage for the aldose reductase inhibitors of this invention is in therange of about 0.01 mg/kg/day to 100 mg/kg/day in single or divideddoses, preferably 0.1 mg/kg/day to 20 mg/kg/day in single or divideddoses and the selective COX-2 inhibitor will be administered in singleor divided doses. Selective COX-2 inhibitors will generally beadministered in amounts ranging from about 0.01 mg/kg/day in single ordivided doses, preferably 10 mg to about 300 mg per day for an averagesubject, depending upon the selective COX-2 inhibitor and the route ofadministration. However, some variation in dosage will necessarily occurdepending on the condition of the subject being treated. The personresponsible for administration will, in any event, determine theappropriate dose for the individual subject.

Administration of the pharmaceutical compositions of this invention canbe via any method which delivers a composition of this inventionpreferentially to the desired tissue (e.g., nerve, kidney, retina and/orcardiac tissues). These methods include oral routes, parenteral,intraduodenal routes, etc. Generally, the compositions of the presentinvention are administered in single (e.g., once daily) or multipledoses or via constant infusion.

Pharmaceutical compositions comprising an aldose reductase inhibitor, aprodrug thereof or a pharmaceutically acceptable salt of said aldosereductase inhibitor or said prodrug and a selective COX-2 inhibitor, aprodrug thereof or a pharmaceutically acceptable salt of said selectiveCOX-2 inhibitor or said prodrug are hereinafter referred to,collectively, as “the active compositions of this invention.”

The active compositions of this invention may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, the activecompositions of this invention may be administered intranasally, as arectal suppository or using a “flash” formulation, i.e., allowing themedication to dissolve in the mouth without the need to use water.

The active compositions of this invention may be administered alone orin combination with pharmaceutically acceptable carriers, vehicles ordiluents, in either single or multiple doses. Suitable pharmaceuticalcarriers, vehicles and diluents include inert solid diluents or fillers,sterile aqueous solutions and various organic solvents. Thepharmaceutical compositions formed by combining the active compositionsof this invention and the pharmaceutically acceptable carriers, vehiclesor diluents are then readily administered in a variety of dosage formssuch as tablets, powders, lozenges, syrups, injectable solutions and thelike. These pharmaceutical compositions can, if desired, containadditional ingredients such as flavorings, binders, excipients and thelike. Thus, for purposes of oral administration, tablets containingvarious excipients such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch, alginic acid and certain complex silicates, together withbinding agents such as polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules. Preferred materials for thisinclude lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyesand, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin andcombinations thereof.

For parenteral administration, solutions of the active compositions ofthis invention in sesame or peanut oil, aqueous propylene glycol, or insterile aqueous solutions may be employed. Such aqueous solutions shouldbe suitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. These particular aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal administration. In this connection, thesterile aqueous media employed are all readily available by standardtechniques known to those skilled in the art.

Generally, a composition of this invention is administered orally, orparenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disordersor whenever the medication is best applied to the surface of a tissue ororgan as determined by the attending physician.

For buccal administration the composition (two active agentsadministered together or separately) may take the form of tablets orlozenges formulated in a conventional manner.

For intranasal administration or administration by inhalation, theactive compounds of the invention (two active agents administeredtogether or separately) are conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

For purposes of transdermal (e.g.,topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

The active compositions of this invention contain an amount of both analdose reductase inhibitor, a prodrug thereof or a pharmaceuticallyacceptable salt of said aldose reductase inhibitor or said prodrug and aselective COX-2 inhibitor, a prodrug thereof or a pharmaceuticallyacceptable salt of said selective COX-2 inhibitor or said prodrug. Theamount of each of those ingredients may independently be, for example,0.0001 %-95% of the total amount of the composition, where the totalamount of each may not, of course, exceed 100%. In any event, thecomposition or formulation to be administered will contain a quantity ofeach of the components of the composition according to the invention inan amount effective to treat the disease/condition of the subject beingtreated.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: an aldosereductase inhibitor, a prodrug thereof or a salt of such aldosereductase inhibitor or prodrug and a selective COX-2 inhibitor, aprodrug thereof or a salt of said selective COX-2 inhibitor or prodrugas described above. The kit comprises a container for containing theseparate compositions such as a divided bottle or a divided foil packet.Typically the kit comprises directions for the administration of theseparate components. The kit form is particularly advantageous when theseparate components are preferably administered in different dosageforms (e.g., oral and parenteral), are administered at different dosageintervals, or when titration of the individual components of thecombination is desired by the prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc . . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of the aldose reductaseinhibitor can consist of one tablet or capsule while a daily dose of theCOX-2 inhibitor can consist of several tablets or capsules and viceversa. The memory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compositions of this invention generally will be administered in aconvenient formulation. The following formulation examples areillustrative only and are not intended to limit the scope of the presentinvention.

In the formulations which follow, “active ingredient” means acombination of the compounds of this invention.

Formulation 1: Gelatin Capsules

Hard gelatin capsules are prepared using the following:

Ingredient Quantity (mg/capsule) Active ingredient 0.25-100   Starch, NF 0-650 Starch flowable powder 0-50 Silicone fluid 350 centistokes 0-15

A tablet formulation is prepared using the ingredients below:

Formulation 2: Tablets

Ingredient Quantity (mg/tablet) Active ingredient 0.25-100   Cellulose,microcrystalline 200-650  Silicon dioxide, fumed 10-650 Stearate acid5-15

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.25-100 mg of active ingredientsare made up as follows:

Formulation 3: Tablets

Ingredient Quantity (mg/tablet) Active ingredient 0.25-100 Starch 45Cellulose, microcrystalline 35 Polyvinylpyrrolidone (as 10% solution inwater) 4 Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5 Talc1

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 mldose are made as follows:

Formulation 4: Suspensions

Ingredient Quantity (mg/5 ml) Active ingredient 0.25-100 mg Sodiumcarboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10mL Flavor q.v. Color q.v. Purified Water to 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume. An aerosol solution is preparedcontaining the following ingredients:

Formulation 5: Aerosol

Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75Propellant 22 (chlorodifluoromethane) 74.00

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container. Suppositories are prepared as follows:

Formulation 6: Suppositories

Ingredient Quantity (mg/suppository) Active ingredient 250 Saturatedfatty acid glycerides 2,000  

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7: Intravenous Solution

Ingredient Quantity Active ingredient 25 mg-10,000 mg Isotonic saline1,000 mL

The solution of the above ingredients is intravenously administered to apatient.

What is claimed is:
 1. A pharmaceutical composition comprising an aldosereductase inhibitor (ARI), a prodrug thereof or a pharmaceuticallyacceptable salt of said ARI or said prodrug and a selective COX-2inhibitor of formula I,

wherein R¹ is sulfamyl; R² is haloalkyl; R³ is selected from hydrido andalkyl; and R⁴ is selected from aryl, cycloalkyl and cycloalkenyl;wherein R⁴ is optionally substituted at a substitutable position withone or more radicals selected from halo, alkylthio, alkylsulfinyl,alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido,N-monoalkylamido, N-monoarylamido, N,N-dialkylamido,N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl,haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino,N,N-dialkylamino, heterocyclic, nitro and acylamino, or a prodrugthereof or a pharmaceutically acceptable salt of said selective COX-2inhibitor of formula I or of said prodrug.
 2. A composition of claim 1wherein said selective COX-2 inhibitor is celecoxib, a prodrug thereofor a pharmaceutically acceptable salt of celecoxib or said prodrug orvaldecoxib, a prodrug thereof or a pharmaceutically acceptable salt ofvaldecoxib or said prodrug.
 3. A composition of claim 2 wherein said ARIis fidarestat, epalrestat, minalrestat, SPR-210, zenarastat orzopolrestat, a prodrug of said compound or a pharmaceutically acceptablesalt of said ARI or said prodrug.
 4. A composition of claim 3 whereinsaid ARI is zopolrestat, a prodrug thereof or a pharmaceuticallyacceptable salt of zopolrestat or said prodrug.
 5. A composition ofclaim 4 wherein said selective COX-2 inhibitor is valdecoxib, a prodrugthereof or a pharmaceutically acceptable salt of valdecoxib or saidprodrug.
 6. A composition of claim 4 wherein said selective COX-2inhibitor is celecoxib, a prodrug thereof or a pharmaceuticallyacceptable salt of celecoxib or said prodrug.
 7. A method of treating amammal suffering from a diabetic complication comprising administeringto said mammal a pharmaceutical composition of claim
 1. 8. A method ofclaim 7 wherein said diabetic complication is diabetic neuropathy,diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy,cataracts or myocardial infarction.
 9. A method of treating a mammalsuffering from a diabetic complication comprising administering to saidmammal a pharmaceutical composition of claim
 2. 10. A kit comprising: a)a first unit dosage form comprising an aldose reductase inhibitor (ARI),a prodrug thereof or a pharmaceutically acceptable salt of said ARI orsaid prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent; b) a second unit dosage form comprising a selective COX-2inhibitor of formula I,

 wherein R¹ is sulfamyl; R² is haloalkyl; R³ is selected from hydridoand alkyl; and R⁴ is selected from aryl, cycloalkyl and cycloalkenyl;wherein R⁴ is optionally substituted at a substitutable position withone or more radicals selected from halo, alkylthio, alkylsulfinyl,alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido,N-monoalkylamido, N-monoarylamido, N,N-dialkylamido,N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl,haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino,N,N-dialkylamino, heterocyclic, nitro and acylamino, or a prodrugthereof or a pharmaceutically acceptable salt of said selective COX-2inhibitor of formula I or said prodrug; and c) a container.
 11. A methodof treating a diabetic complication in a mammal comprising administeringto said mammal an ARI, a prodrug thereof or a pharmaceuticallyacceptable salt of said ARI or said prodrug and a selective COX-2inhibitor of formula I

wherein R¹ is sulfamyl; R² is haloalkyl; R³ is selected from hydrido andalkyl; and R⁴ is selected from aryl, cycloalkyl and cycloalkenyl;wherein R⁴ is optionally substituted at a substitutable position withone or more radicals selected from halo, alkylthio, alkylsulfinyl,alkyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, amido,N-monoalkylamido, N-monoarylamido, N,N-dialkylamido,N-alkyl-N-arylamido, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl,haloalkoxy, sulfamyl, N-alkylsulfamyl, amino, N-alkylamino,N,N-dialkylamino, heterocyclic, nitro and acylamino, a prodrug thereofor a pharmaceutically acceptable salt of said selective COX-2 inhibitorof formula I or said prodrug.
 12. A method of claim 11 wherein said ARIis fidarestat, epalrestat, minalrestat, SPR-210, zenarastat orzopolrestat, a prodrug thereof or a pharmaceutically acceptable saltthereof or of said prodrug.
 13. A method of claim 12 wherein said ARI iszopolorestat, a prodrug thereof or a pharmaceutically acceptable salt ofzopolrestat or said prodrug; and said COX-2 inhibitor is celecoxib, aprodrug thereof or a pharmaceutically acceptable salt of celecoxib orsaid prodrug.
 14. A method of claim 12 wherein said ARI is zopolorestat,a prodrug thereof or a pharmaceutically acceptable salt of zopolrestator said prodrug; and said COX-2 inhibitor is valdecoxib, a prodrugthereof or a pharmaceutically acceptable salt of valdecoxib or saidprodrug.